The principal focus of these studies has been mechanisms for resistance to virus persistently infected tumor cells. We have demonstrated that strains of normal and nude mice possess cells capable of spontaneous cytotoxicity of a variety of virus persistently infected tumor cells, and that such tumor cells fail to grow in nude mice. The cell responsible appears to be an NK cell. We have characterized the phenotype of this NK cell as Qa 5 plus Ly 5 plus, and shown that one mode of regulation of NK cell activity by IFN is to cause the differentiation of a non-cytotoxic Qa 5 plus Ly 5 minus precursor into a Qa 5 plus NK effector cell. The role of the IFN-NK system in rejection of virus infected tumor cells or primary human tumors in nude mice has been tested critically by use of anti-mouse IFN sera. Nude mice treated with a single dose of anti-IFN serum were able to grow virus persistently infected xenogenic tumor cells, whereas untreated nude mice rejected them, thereby indicating that interferon was acting indirectly to alter the host response, presumably NK cells. In addition, we were able for the first time to grow two primary human prostatic adenocarcinomas in nude mice treated with anti-interferon, from which one may infer that the failure of some human tumors to grow in nude mice was due to their rejection of the IFN-NK system. Infection of lymphoid cells with measles virus invariably resulted in virus persistently infected cell cultures. Virus clones isolated from such cultures were found to be overwhelmingly ts mutant. Use of monoclonal antibodies directed at measles virus polypeptides, particularly the hemagglutinin, were used to select antigenic variants of measles virus for the first time. The variants were isolated, and the altered polypeptides were identified by peptide mapping, proving they were mutant. Thus it was shown that mutant viruses can be generated by lymphoid cells, and in the presence of antibody selection, antigenic variants can be obtained.